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  • Furthermore elastase might not be the

    2019-11-26

    Furthermore, elastase might not be the only regulator of CBG on cleaved and uncleaved form. In a study by Nenke et al. [85] α1-AT deficient subjects, who lack this native neutrophil elastase inhibitor, paradoxically have higher levels of uncleaved CBG and lower levels of CBG* [85]. Gender differences are present in the levels of the steroid hormones progesterone [8] and testosterone [9], but also in the levels of CBG [45]. The rise in ABT-199 and testosterone during pregnancy is often ascribed to the rise in the transport proteins CBG and sex hormone binding globulin (SHBG) [13]. However, the total concentration of cortisol is not solely controlled by the level of its transport proteins, since higher levels of CBG is seen in women compared to men [45], while higher levels of total cortisol is reported the same [86] or even higher [87] in men compared to women. In subjects homozygote for a non-functioning CBG variant Perogamvros et al. [88] found similar free cortisol concentrations, but decreased glucocorticoid bioactivities when comparing these to subjects heterozygote for the CBG mutation and healthy controls [88]. When comparing the predictions of the different models for six example persons with estimated total levels of the input variables corresponding to different age and gender, it becomes clear that the models disagree on the distribution of cortisol in bound forms as well as their predictions for free cortisol (see Fig. 7). The most dramatic differences are seen in the predictions by Coolens et al. [1] for pregnant women and COCP women compared to the other models. Ho et al. [89] finds that the formulae by Coolens et al. [1] is not valid for calculating free cortisol in pregnant women [89]. Traditionally only free cortisol is considered bioactive and that the dissociations of cortisol from both albumin and CBG happen quite fast [90]. There has been speculation on a CBG receptor taking part in the activity of cortisol [91]. Hence, maybe not only the models predictions on free cortisol should be taken into consideration, but also the predictions on the distribution of bound cortisol. Cortisol is secreted in ultradian pulses of approximately 1–2 h period and with large amplitudes compared to their average values [92], [93]. By using a static equilibrium solution we assume that the equilibrium between the transport proteins and steroids occurs rapidly. This assumption is often applied in both methods for estimating free cortisol [2] and in dynamical models of the hypothalamic–pituitary–adrenal (hpa) axis [94]. Furthermore, by Eq. (1) we assume equilibrium between the elimination and enzymatic synthesis of CBG*. As discussed above the activity of elastase could differ greatly between the blood and sites of inflammation. The dynamical model by Nguyen et al. [3] is in the time scale of seconds, but they do not relate their work to the ultradian and circadian oscillations present in the system. In an ongoing work we are exploring a dynamical version of the underlying mass action model to see whether these assumptions hold and how the interaction of cortisol with plasma proteins in the blood influences the oscillating nature of cortisol.
    Conflict of interest
    Acknowledgements We would like to thank Prof. Dr. Richard I. Dorin for helpful discussions on parameter values. This research was supported by funding from The Danish Society for the Protection of Laboratory Animals and from Alternativfondet.
    Methods
    Results
    Discussion Macrophages play a critical role in AAA pathogenesis from initial development to growth and occurrence of rupture through regulation of ECM ABT-199 remodeling, inflammatory response, oxidative stress, and tissue repair. Given their role in AAA, targeting of macrophages could lead to the development of innovative therapeutic strategies. We aimed to study the phenotype of macrophages in an elastase + anti-TGF-β-induced AAA model as well as to define which genes in the aorta can be attributed to macrophage infiltration by using a focused and meaningful strategy of depletion/qPCR and flow cytometry. We found that TGF-β neutralization after elastase injury on the aorta induced changes in the expression of M1 and M2 markers and led to an increase of macrophages expressing ARG1. Interestingly, the proportion of macrophages expressing ARG1 increased with aneurysmal dilation in mice.